Method for realizing Suzuki-Miyaura coupling of aryl thianthrene onium salt based on micro-flow field technology

Abstract

The invention belongs to the field of organic chemical synthesis, and relates to a method for realizing Suzuki-Miyaura coupling of aryl thianthrene onium salt based on a micro-flow field technology. The method comprises the following steps: mixing aryl thianthrene onium salt, a phenylboronic acid compound, a catalyst and a solvent to obtain a mixed solution; and pumping the mixed solution into a micro-flow field reactor of the micro-flow field reaction device, and carrying out a coupling reaction to obtain the aryl product. According to the method, the aryl thianthrene onium salt and the phenylboronic acid compound are used as raw materials, under the action of the catalyst, the aryl product is synthesized through coupling by adopting a micro-flow field reaction technology, and the yield of the aryl product reaches up to 98%; and under the same level, by adopting a conventional reaction kettle, the yield of the aryl product is only 60%. The micro-flow field reaction technology is adopted, so that the problems of complicated operation, long reaction time, need of expensive catalyst, low atom economic efficiency and the like in the traditional synthesis reaction can be effectively solved.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis, and relates to a method for realizing Suzuki-Miyaura coupling of aryl thianthrenium salts based on microfluidic technology. Background Art

[0002] The palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction is currently the most common method for constructing carbon-carbon bonds in the pharmaceutical industry. However, traditional reaction conditions often require the participation of bases, which limits the scope of its substrates. To overcome this limitation, researchers have developed alkali-resistant organoboron reagents, highly efficient catalysts, and reaction conditions that do not require the participation of external bases to achieve the Suzuki-Miyaura cross-coupling reaction. For example, the prior art (Journal of the American Chemical Society, 2010, 132, 14073-14075) discloses a Pd-XPhos catalyst, which enables the cross-coupling reaction of 2-thienylboronic acid without the participation of a base. The prior art (Nature, 2018, 563, 100-104) discloses the nickel-catalyzed SMC reaction of benzoyl fluoride under neutral reaction conditions. Although researchers have made progress in aspects such as acidic buffer conditions, the SMC reaction still faces challenges such as long reaction time, cumbersome reaction process, and low reaction yield. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for realizing Suzuki-Miyaura coupling of aryl thianthrenium salts based on microfluidic technology in view of the deficiencies of the prior art, so as to solve the problems of cumbersome reaction process, low reaction yield, low atom utilization rate, and difficulty in large-scale synthesis existing in the prior art.

[0004] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0005] The present invention discloses a method for realizing Suzuki-Miyaura coupling of aryl thianthrenium salts based on microfluidic technology. An aryl thianthrenium salt, a phenylboronic acid compound, a palladium catalyst, and a solvent are mixed to obtain a mixed solution; the mixed solution is pumped into a microfluidic reactor of a microfluidic reaction device for a coupling reaction to obtain an aryl product;

[0006] Among them, the structural formula of the aryl thianthrenium salt is shown in Formula 1, and the structural formula of the phenylboronic acid compound is as

[0007] shown in Formula 2, and the structural formula of the aryl product is shown in Formula 3:

[0008]

[0009] Among them,

[0010] is selected from phenyl, thienyl, furyl or biphenyl;

[0011] n is an integer between 0 and 4;

[0012] R1 is selected from phenoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl or halogen;

[0013] R2 is selected from substituted or unsubstituted phenyl;

[0014] Among them, the substitution is selected from being substituted by 1 to 4 identical or different substituents; the substituents are selected from halogen, C1-C8 alkyl or nitro.

[0015] In some embodiments, preferably,

[0016] is selected from phenyl, thienyl or biphenyl;

[0017] n is an integer between 0 and 2;

[0018] R1 is selected from phenoxy, substituted or unsubstituted C3-C8 alkyl, substituted or unsubstituted C1-C2 alkoxy, substituted or unsubstituted C5-C6 cycloalkyl or halogen;

[0019] R2 is selected from substituted or unsubstituted phenyl;

[0020] Among them, the substitution is selected from being substituted by 1 to 4 identical or different substituents; the substituents are selected from halogen, C1-C4 alkyl or nitro.

[0021] In some embodiments, further preferably,

[0022] is selected from phenyl, thienyl or biphenyl;

[0023] n is an integer between 1 and 2;

[0024] R1 is selected from phenoxy, n-propyl, n-octyl, ethoxy, cyclohexyl, fluorine, chlorine or bromine;

[0025] R2 is selected from substituted or unsubstituted phenyl;

[0026] Among them, the substitution is selected from being substituted by fluorine, chlorine, bromine, tert-butyl or nitro.

[0027] In some embodiments, the palladium catalyst is any one or a combination of several of bis(tri-tert-butylphosphine)palladium(0), tetrakis(triphenylphosphine)palladium and palladium acetate.

[0028] In some embodiments, preferably, the palladium catalyst is bis(tri-tert-butylphosphine)palladium(0).

[0029] In some embodiments, the solvent is any one or a combination of several of acetonitrile, dichloroethane, dimethyl sulfoxide, N,N-dimethylacetamide, methanol, ethanol, tetrahydrofuran, and 1,4-dioxane.

[0030] In some embodiments, preferably, the solvent is any one or a combination of several of methanol, dimethyl sulfoxide, ethanol, tetrahydrofuran, and 1,4-dioxane.

[0031] In some embodiments, the molar ratio of the arylthianthrenium salt to the phenylboronic acid compound is 1.0:(1.0 - 3.0).

[0032] In some embodiments, preferably, the molar ratio of the arylthianthrenium salt to the phenylboronic acid compound is 1.0:1.5.

[0033] In some embodiments, the molar ratio of the arylthianthrenium salt to the palladium catalyst is 1.00:(0.05 - 0.25).

[0034] In some embodiments, preferably, the molar ratio of the arylthianthrenium salt to the palladium catalyst is 1.00:(0.05 - 0.15), more preferably 1.00:(0.05 - 0.10), still more preferably 1.00:(0.05 - 0.08), and most preferably 1.00:0.05.

[0035] In some embodiments, in the mixed solution, the concentration of the arylthianthrenium salt is 0.01 - 0.20 mmol / mL.

[0036] In some embodiments, preferably, in the mixed solution, the concentration of the arylthianthrenium salt is 0.05 - 0.15 mmol / mL, more preferably 0.05 - 0.10 mmol / mL, still more preferably 0.05 - 0.08 mmol / mL, and most preferably 0.05 mmol / mL.

[0037] In some embodiments, for the coupling reaction, the reaction temperature is 40°C - 80°C.

[0038] In some embodiments, preferably, for the coupling reaction, the reaction temperature is 50°C - 70°C, and more preferably 60°C.

[0039] In some embodiments, for the coupling reaction, the reaction residence time in the microfluidic reactor is 5 min - 60 min.

[0040] In some embodiments, preferably, for the coupling reaction, the residence time in the microfluidic reactor is 20 min to 40 min, more preferably 30 min.

[0041] In some embodiments, the microfluidic reaction device includes a connecting pipe, a feed pump, a microfluidic reactor, and a receiver; wherein, the feed pump, the microfluidic reactor, and the receiver are connected in series through the connecting pipe in sequence.

[0042] Among them, the microfluidic reactor is a tubular reactor, the inner diameter of the pipe is 0.5 mm to 3.0 mm, preferably 1.0 mm.

[0043] The aryl product shown in Formula 3 obtained in the present invention can be applied to the specific site modification of aryl compounds in synthetic design.

[0044] Beneficial effects:

[0045] (1) In the present invention, using aryl thianthrenium salts and phenylboronic acid compounds as raw materials, under the action of a palladium catalyst, a microfluidic reaction technology is adopted for coupling synthesis of aryl products, and the yield of the aryl product is as high as 98%; at the same level, using a conventional reaction kettle, the yield of the aryl product is only 60%. The microfluidic reaction technology can effectively overcome the problems existing in traditional synthesis reactions, such as complex operation, long reaction time, the need for expensive palladium catalysts, and low atom economic efficiency.

[0046] (2) The present invention uses an inexpensive metal palladium catalyst and a low-toxic solvent, thereby reducing the synthesis cost, and the reaction conditions are green and environmentally friendly.

[0047] (3) Compared with the prior art, in the present application, there is no need to add substances such as alkali. The present invention uses an inexpensive and easily available palladium reagent as a catalyst, and a palladium ion pair stable to acid is formed in the coupling reaction, and this palladium ion pair does not require alkali for subsequent transmetalation. Description of the drawings

[0048] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0049] Figure 1 It is a microfluidic reaction device diagram used in the embodiment of the present invention.

[0050] Figure 2 It is the 1H NMR spectrum of 4-phenoxy-1,1'-biphenyl.

[0051] Figure 3 It is the 13C NMR spectrum of 4-phenoxy-1,1'-biphenyl. Specific embodiments

[0052] The present invention can be better understood according to the following embodiments. However, those skilled in the art can easily understand that the content described in the embodiments is only used to illustrate the present invention, and should not and will not limit the present invention detailed in the claims.

[0053] In the following embodiments, the experimental methods are conventional methods unless otherwise specified; the reagents and materials can be obtained from commercial sources unless otherwise specified.

[0054] 1. The microfluidic reaction device used in the embodiments of the present invention is shown in Figure 1 , and the microfluidic reaction device includes a connecting pipe, a feeding pump, a microfluidic reactor, and a receiver; wherein, the feeding pump, the microfluidic reactor, and the receiver are connected in series through the connecting pipe in sequence.

[0055] Among them, the model of the feeding pump is Baoding Leifu Fluid Technology Co., Ltd., TYDO1-01 CE type.

[0056] Among them, the microfluidic reactor adopts a pore structure design, and the pore material is perfluoroalkoxy alkane (PFA); the inner diameter of the microfluidic reactor is 1.0 mm, and the volume is 2 mL.

[0057] Among them, the reaction temperature of the microfluidic reactor is heated by oil bath of an oil bath pot.

[0058] 2. The arylthianthrenium salt used in the embodiments of the present invention can be prepared according to the prior art (Qin, Long-Zhou; Sun, Hao; Duan, Xiu; et al. Visible-light-induced nickel-catalyzed selective S-arylation of peptides by exogenous-photosensitizer-free photocatalysis [J]), or can be prepared according to the following preparation method:

[0059]

[0060] Among them, is selected from phenyl, thienyl, furyl or biphenyl; n is an integer between 0 and 4; R1 is selected from phenoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl or halogen.

[0061] The aryl compound (10.0 mmol, 1.0 equiv.) was mixed with acetonitrile, and then trifluoroacetic anhydride (42 mL, 30.0 mmol, 3.0 equiv.) was added. The reaction system was placed under the condition of 0 °C. At this temperature, TTO (2.32 g, 10.0 mmol, 1.0 equiv.) was added in one portion, and then HBF4·Et2O (1.6 mL, 120 mmol, 1.2 equiv.) was added. The reaction solution was stirred at 0 °C for 1 hour, and then transferred to room temperature and continued to react for 2 - 15 hours. After the reaction was completed, acetonitrile was removed by rotary evaporation, diluted with dichloromethane, quenched with saturated sodium bicarbonate solution, and further extracted with dichloromethane. The combined organic layers were washed with 10% NaBF4 and dried over anhydrous sodium sulfate. Finally, the solvent was removed by distillation under reduced pressure. The obtained crude product was purified by silica gel column chromatography analysis to obtain a pure arylthianthrenium salt reagent.

[0062] 3. Bis(tri-tert-butylphosphine)palladium(0) used in the examples of the present invention is abbreviated as Pd( t Bu3P)2.

[0063] Example 1:

[0064]

[0065] 5-(4-Phenoxyphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate (0.1 mmol, 1.0 equiv.), phenylboronic acid (0.15 mmol, 1.5 equiv.), and Pd( t Bu3P)2 (0.005 mmol, 0.05 equiv.) were weighed successively, and 2.0 mL of methanol was added and stirred well to dissolve them to obtain a mixed solution.

[0066] The mixed solution was transferred to a syringe, and pumped into the microfluidic reactor (2.0 mL) of the microfluidic reaction device at a flow rate of 0.067 mL / min through an injection pump for a coupling reaction. The residence time of the reaction in the microfluidic reactor was 30 min, and the reaction temperature was 60 °C. The effluent was monitored by thin layer chromatography (TLC). After the reaction was completed, the reaction was quenched, and then extracted three times (50 mL) with dichloromethane and saturated brine. After combining the organic phases, they were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Finally, separation and purification were carried out by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain the product 4-phenoxy-1,1'-biphenyl (Compound 3aa) with a yield of 98%.

[0067] The NMR and mass spectrometry data of 4-phenoxy-1,1'-biphenyl are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.51–7.46 (m, 4H), 7.38–7.33 (m, 2H), 7.31–7.26 (m, 2H), 7.26–7.20 (m, 1H), 7.07–7.02 (m, 1H), 7.02–6.95 (m, 4H). 13 13C NMR (101 MHz, Chloroform-d) δ 157.2, 156.9, 140.6, 136.3, 129.8, 128.8, 128.5, 127.1, 126.9, 123.4, 119.1. HRMS (ESI) m / z: calcd for C 18 H 14 ONa [M+Na] + : 269.0937, found: 269.0928. The 1H NMR spectrum of 4-phenoxy-1,1'-biphenyl is shown in Figure 2 , and the 13C NMR spectrum is shown in Figure 3 .

[0068] Example 2:

[0069]

[0070] The experimental method was the same as that in Example 1, except that 5-(4-octylphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate was used as the raw material, and finally 4-octyl-1,1'-biphenyl (Compound 3ba) was prepared with a yield of 90%.

[0071] The NMR and mass spectrometry data of 4-octyl-1,1'-biphenyl are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 8 Hz, 2H), 7.51 (d, J = 8 Hz, 2H), 7.42 (t, J = 8 Hz, 2H), 7.32 (t, J = 8 Hz, 1H), 7.27–7.24 (m, 2H), 2.64 (t, J = 8 Hz, 2H), 1.65 (q, J = 8 Hz, 2H), 1.37–1.26 (m, 10H), 0.88 (t, J = 8 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 142.2, 141.2, 138.5, 128.9, 128.7, 127.0, 127.0, 127.0, 35.7, 32.0, 31.6, 29.6, 29.4, 29.3, 22.7, 14.2. HRMS (ESI) m / z: calcd for C 20 H 26 Na [M+Na]+ : 289.1927, found: 289.1916.

[0072] Example 3:

[0073]

[0074] The experimental method was the same as that of Example 1, except that 5-(4-ethoxyphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate was used as the raw material, and 4-ethoxy-1,1'-biphenyl (Compound 3ca) was finally prepared with a yield of 92%.

[0075] The NMR and mass spectrometry data of 4-ethoxy-1,1'-biphenyl are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.58–7.53 (m, 2H), 7.53–7.48 (m, 2H), 7.45–7.36 (m, 2H), 7.34–7.26 (m, 1H), 7.00–6.92 (m, 2H), 4.08 (q, J = 8.0 Hz, 2H), 1.44 (t, J = 8.0 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 158.5, 140.9, 133.6, 128.7, 128.2, 126.7, 126.6, 114.8, 63.5, 14.9. HRMS (ESI) m / z: calcd for C 14 H 14 O Na [M+Na] + : 221.0937, found: 221.0924.

[0076] Example 4:

[0077]

[0078] The experimental method was the same as that of Example 1, except that 5-(4-cyclohexylphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate was used as the raw material, and 4-cyclohexyl-1,1'-biphenyl (Compound 3da) was finally prepared with a yield of 40%.

[0079] The NMR and mass spectrometry data of 4-cyclohexyl-1,1'-biphenyl are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.65–7.48 (m, 4H), 7.47–7.36 (m, 2H), 7.37–7.25 (m, 3H), 2.60–2.47 (m, 1H), 1.98–1.82 (m, 4H), 1.72–1.05 (m, 6H).13 C NMR (101 MHz, Chloroform-d) δ 147.3, 141.2, 138.8, 128.7, 127.3, 127.1, 127.1, 127.0, 44.3, 34.5, 27.0, 26.2. HRMS (ESI) m / z: calcd for C 18 H 20 Na[M+Na] + : 259.1457., found: 259.1465.

[0080] Example 5:

[0081]

[0082] The experimental method was the same as that in Example 1, except that 5-(4-propylphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate was used as the raw material, and finally 4-propyl-1,1'-biphenyl (Compound 3ea) was prepared with a yield of 87%.

[0083] The NMR and mass spectrometry data of 4-propyl-1,1'-biphenyl are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.61–7.57 (m, 2H), 7.56–7.47 (m, 2H), 7.45–7.40 (m, 2H), 7.36–7.29 (m, 1H), 7.27–7.24 (m, 2H), 2.67–2.57 (m, 2H), 1.73–1.63 (m, 2H), 0.97 (t, J = 8 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 141.9, 141.2, 138.6, 128.9, 128.9, 128.8, 128.7, 127.3, 127.2, 127.0, 127.0, 127.0, 126.8, 37.7, 24.6, 14.0. HRMS (ESI) m / z: calcd for C 15 H 16 Na[M+Na] + : 219.1144, found: 219.1132.

[0084] Example 6:

[0085]

[0086] The experimental method was the same as that in Example 1, except that 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate was used as the raw material, and 4-bromo-1,1':4',1'-terphenyl (Compound 3fa) was finally prepared with a yield of 54%.

[0087] The NMR and mass spectrometry data of 4-bromo-1,1':4',1'-terphenyl are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.68(d,J=4Hz,2H),7.66–7.61(m,4H),7.61–7.55(m,2H),7.53–7.49(m,2H),7.49–7.43(m,2H),7.40–7.34(m,1H). 13 C NMR(101MHz,Chloroform-d)δ140.6,140.5,139.6,138.9,132.0,128.9,128.6,127.7,127.5,127.3,127.1,121.6.HRMS(ESI)m / z:calcd forC 18 H 13 BrNa[M+Na] + :331.0093,found:331.0078.

[0088] Example 7:

[0089]

[0090] The experimental method was the same as that in Example 1, except that 5-(4-phenoxyphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate and 4-fluorobenzeneboronic acid were used as the raw materials, and 4-fluoro-4'-phenoxy-1,1'-biphenyl (Compound 3ab) was finally prepared with a yield of 83%.

[0091] The NMR and mass spectrometry data of 4-fluoro-4'-phenoxy-1,1'-biphenyl are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.52–7.50(m,2H),7.50–7.46(m,2H),7.38–7.33(m,2H),7.14–7.07(m,4H),7.06(d,J=4Hz,1H),7.06–7.04(m,2H). 1313C NMR (101 MHz, Chloroform-d) δ 163.6, 161.1, 157.1, 156.9, 136.7, 136.7, 135.3, 129.9, 128.5, 128.4, 128.3, 123.5, 119.1, 119.1, 115.8, 115.6. HRMS (ESI) m / z: calcd for C 18 H 13 FONa [M+Na] + : 287.0843, found: 287.0856.

[0092] Example 8:

[0093]

[0094] The experimental method was the same as that in Example 1, except that 5-(4-phenoxyphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate and 4-(tert-butyl)phenylboronic acid were used as raw materials, and finally 4-(tert-butyl)-4'-phenoxy-1,1'-biphenyl (Compound 3ac) was prepared with a yield of 96%.

[0095] The NMR and mass spectrometry data of 4-(tert-butyl)-4'-phenoxy-1,1'-biphenyl are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 7.58–7.52 (m, 2H), 7.52–7.49 (m, 2H), 7.47–7.44 (m, 2H), 7.38–7.32 (m, 2H), 7.14–7.08 (m, 1H), 7.08–7.03 (m, 4H), 1.36 (s, 9H). 13 13C NMR (101 MHz, Chloroform-d) δ 157.2, 156.6, 150.1, 137.7, 136.2, 129.8, 128.3, 126.6, 125.8, 123.4, 119.0, 34.6, 31.4. HRMS (ESI) m / z: calcd for C 22 H 22 ONa [M+Na] + : 325.1563, found: 325.1546.

[0096] Example 9:

[0097]

[0098] The experimental method was the same as that in Example 1, except that 5-(3,4-dibromothiophen-2-yl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate was used as the raw material, and finally 3,4-dibromo-2-phenylthiophene (Compound 3ga) was prepared with a yield of 80%.

[0099] The NMR and mass spectrometry data of 3,4-dibromo-2-phenylthiophene are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.63–7.59(m,2H),7.47–7.40(m,3H),7.38(s,1H). 13 C NMR(101MHz,Chloroform-d)δ139.5,133.0,129.0,128.9,128.7,122.4,114.8,111.4.HRMS(ESI)m / z:calcd for C 10 H6Br2SNa[M+Na] + :338.8449,found:338.8454.

[0100] Example 10:

[0101]

[0102] The experimental method was the same as that in Example 1, except that 5-(4-phenoxyphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate and 4-nitro-phenylboronic acid were used as the raw materials, and finally 4-nitro-4'-phenoxy-1,1'-biphenyl (Compound 3ad) was prepared with a yield of 79%.

[0103] The NMR and mass spectrometry data of 4-nitro-4'-phenoxy-1,1'-biphenyl are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.31–8.27(m,2H),7.73–7.69(m,2H),7.62–7.58(m,2H),7.42–7.36(m,2H),7.20–7.15(m,1H),7.13–7.10(m,2H),7.09–7.06(m,2H). 13 C NMR(101MHz,Chloroform-d)δ158.5,156.4,147.0,146.8,133.4,130.0,128.8,127.40,124.2,124.00,119.5,119.0.HRMS(ESI)m / z:calcd for C 18 H 13 NO3Na[M+Na]+ : 314.0788, found: 314.0776.

[0104] Example 11:

[0105] The experimental method was the same as that of Example 1, except that the catalysts were tetrakis(triphenylphosphine)palladium and palladium acetate, respectively. The specific results are shown in Table 1.

[0106] Table 1

[0107] tetrakis(triphenylphosphine)palladium palladium acetate Isolated yield of compound 3aa 83％ 70％

[0108] Example 12:

[0109] The experimental method was the same as that of Example 1, except that the solvents were acetonitrile, dichloroethane, dimethyl sulfoxide, ethanol, tetrahydrofuran, and 1,4-dioxane, respectively. The specific results are shown in Table 2.

[0110] Table 2

[0111] Isolated yield of compound 3aa acetonitrile 3％ dichloroethane 5％ dimethyl sulfoxide 57％ ethanol 87％ tetrahydrofuran 79％ 1,4-dioxane 85％

[0112] Comparative Example 1: Comparative example of Example 1

[0113]

[0114] Take a dry Schlenk reaction tube and sequentially add 5-(4-phenoxyphenyl)-4a,10a-dihydro-5H-thiophen-5-ium tetrafluoroborate (0.1 mmol, 1.0 equiv.), phenylboronic acid (0.15 mmol, 1.5 equiv.), Pd( t (Bu3P)2 (0.005 mmol, 0.05 equiv.), add 2.0 mL of methanol and stir well to dissolve it, and stir the reaction at 60 °C for 6 hours. After the reaction is completed, quench the reaction, and then perform three extractions (50 mL) with dichloromethane and saturated brine. After combining the organic phases, dry with anhydrous sodium sulfate and distill off the solvent under reduced pressure. Finally, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain the product 4-phenoxy-1,1'-biphenyl (Compound 3aa) with a yield of 60%.

[0115] The present invention provides an idea and method for realizing the Suzuki-Miyaura coupling of aryl thianthrenium salts based on microfluidic technology. There are many methods and ways to specifically implement this technical solution. The above description is only the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention. Each component not clearly defined in this embodiment can be realized by the prior art.

Claims

1. A method for realizing Suzuki-Miyaura coupling of aryl thianthrenium salts based on microfluidic field technology, characterized in that: The aryl thianthrenium salt, the phenylboronic acid compound, the palladium catalyst and the solvent are mixed to obtain a mixed solution; the mixed solution is pumped into a microfluidic reactor of a microfluidic reaction device to perform a coupling reaction, thereby obtaining an aryl product; The structural formula of the aryl thianthrenium salt is shown in Formula 1, the structural formula of the phenylboronic acid compound is shown in Formula 2, and the structural formula of the aromatic product is shown in Formula 3: in, is selected from phenyl, thienyl, furanyl or biphenyl; n is an integer between 0 and 4; R1 is selected from phenoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl or halogen; R2 is selected from substituted or unsubstituted phenyl; Wherein, the substitution is selected from substitution by 1 to 4 identical or different substituents; the substituent is selected from halogen, C1 to C8 alkyl or nitro.

2. The method according to claim 1, characterized in that is selected from phenyl, thienyl or biphenyl; n is an integer between 0 and 2; R1 is selected from phenoxy, substituted or unsubstituted C3-C8 alkyl, substituted or unsubstituted C1-C2 alkoxy, substituted or unsubstituted C5-C6 cycloalkyl or halogen; R2 is selected from substituted or unsubstituted phenyl; Wherein, the substitution is selected from substitution by 1 to 4 identical or different substituents; the substituents are selected from halogen, C1 to C4 alkyl or nitro; More preferably, is selected from phenyl, thienyl or biphenyl; n is an integer between 1 and 2; R1 is selected from phenoxy, n-propyl, n-octyl, ethoxy, cyclohexyl, fluorine, chlorine or bromine; R2 is selected from substituted or unsubstituted phenyl; Wherein, the substitution is selected from fluorine, chlorine, bromine, tert-butyl or nitro.

3. The method according to claim 1, characterized in that The palladium catalyst is any one of bis(tri-tert-butylphosphine)palladium(0), tetrakis(triphenylphosphine)palladium and palladium acetate or a combination of several of them.

4. The method according to claim 1, characterized in that: The solvent is any one or a combination of acetonitrile, dichloroethane, dimethyl sulfoxide, N,N-dimethylacetamide, methanol, ethanol, tetrahydrofuran and 1,4-dioxane.

5. The method according to claim 1, characterized in that The molar ratio of the arylthianthrenium salt to the phenylboronic acid compound is 1.0:(1.0-3.0).

6. The method according to claim 1, characterized in that The molar ratio of the arylthianthrenium salt to the palladium catalyst is 1.00:(0.05-0.25).

7. The method according to claim 1, characterized in that In the mixed solution, the concentration of the arylthianthrenium salt is 0.01 to 0.20 mmol / mL.

8. The method according to claim 1, characterized in that The coupling reaction has a reaction temperature of 40°C to 80°C.

9. The method according to claim 1, characterized in that: For the coupling reaction, the reaction residence time in the microfluidic field reactor is 5 min to 60 min.

10. The method according to claim 1, characterized in that The microfluidic field reaction device comprises a connecting pipe, a feed pump, a microfluidic field reactor and a receiver; wherein the feed pump, the microfluidic field reactor and the receiver are sequentially connected in series via the connecting pipe.

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